DIALKYLAMINO  ALKYL  HALIDES 


HY 


OSCAR  DAVID  BLUTHARDT 


THESIS 


FOR  THE 


DEGREE  OF  BACHELOR  OE  SCIENCE 


CHEMISTRY 


COLLEGE  OF  LIBERAL  ARTS  AND  SCIENCES 


UNIVERSITY  OF  ILLINOIS 


1922 


rj  tu  u. 


UNIVERSITY  OF  ILLINOIS 


. _ *.  J-v- _SXi  * 1 9 2§ 


THIS  IS  TO  CERTIFY  THAT  THE  THESIS  PREPARED  UNDER  MY  SUPERVISION  BY 





ENTITLED. 


T -i  f) 


— 


IS  APPROVED  BY  ME  AS  FULFILLING  THIS  PART  OF  THE  REQUIREMENTS  FOR  THE 


DEGREE  OF j Ik i i .. 


LLii ( 


.AIL. 


Instructor  in  Charge 


Approved  : 


;irn  • Ul  7 d-*_  j \ 


HEAD  OF  DEPARTMENT  OF 


( ) 4 


Digitized  by  the  Internet  Archive 
in  2016 


https://archive.org/details/dialkylaminoalkyOOblut 


ACIirO-L^DGI.hlJT. 

The  author  wishes  to  thank  Doctor  Carl  SJdarvel,  under  whose 
supervision  this  work  was  carried  on,  for  the  helpful  suggest- 
ions the  latter  has  offered  during  the  progress  of  the  invest- 
igation and  the  writing  of  the  thesis. 


Introduction. 


IA3L3  OF  CONTENTS. 

Historical  and  Theoretical  Part * 1. 

Experimental  part . 

Phenoxypropyl  diethyl  amine — 4. 

Sromprop3^1  diethyl  amine  hydro  bromide 9. 


Phenoxybutyl  amine la . 

Phenoxybutyl  diethyl  amine ■ 13. 

Broinb-utyl  diethyl  amine,  hydrobromide 14. 

Summary. — — 16. 

Bibliography 17. 


Il 


, of  ipj  -t! 


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* 


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•j  ■ „ MWU  Ui'.  */<  *<**  * t„‘-  *•<  # k t V-*  *i:‘' 


3 . J * > 


iKTHorrjoTroiT 

Very  little  is  known  about  di alkyTamlno  alkyl  halides.  The 
purpose  of  this  investigation  was  to  prepare  diethylarnino  propyl 
bromide  arid  die  thy  lamina  butyl  bromide  and  other  di  alkyl  amino  alkyl 
halides.  This  type  of  compound  would  be  of  interest  in  the 
synthesis  of  compounds  related  to  novacaine  which  has  a local 
anaesthetic  action. 

These  compounds  could  be  studied  in  all  reactions  that  are 

os 

common  to  alkyl  halides  such,  as  Friedel^Craft*  tnd  Grignard^s 
reactions.  They  ould  have  the  additional  value  of  introducing 
dialkylamino  alkyl  groups  where  alkyl  groups  are  put  in  by  the 
use  of  simple  alkyl  halides. 


HISTORICAL  & THSORETIOAL 

Dialkylamino  alkyl  halides  have  not  been  prepared  with  the 
exception  of  brometlrrl  diethvl  amine  which  was  prewared'  bv 

X %J  w>  X i.  1/ 

Meyer  and  Kopffa  by  treating  diethylamino-cthanol  with 
hydro bromic  acid  in  a sealed  tube. 

The  first  step  toward  preparing,  the  brcmpropyl  diethyl  amine 
was  to  prepare  phenoxypr o py 1 diethyl  amine.  Fhenoxypropyl 
bromide  was  used  as  the  starting  material*  One  mole  of  phenoxy— 
propyl  bromide  was  treated  with  one  mole  of  diethyl  amine,  and 
phenoxypropyl  diethyl  amine  and  the  Irwlrobromide  of  diethvl 


amine  were  formed.  It  was  thought  that  one  mole  o^ 
bromide  and  one  mole  of  diethyl  :ine  would  ^ive 
hydro bromide  of  phenoxypropyl  diethyl  amine. 


i phenoxypr 

O X, 


I r,  rs  -p 


the 


H 


^-0-cHa-CH3-CHa-B>r  ca  H5  v M u /\  o-c^CH^-CH^N  " C*-H* 


B r* 


C*  Hs- 


The  reaction  did  not  work  as  was  expected  but  acted  as  follows 


+ K:Z>*" 


0-CH£-C/fa-C/Vx-8ir  ^ + Ca  H 

| 'e*"'  + 

\y  0V_ 

The  reaction  of  one  mole  of  phenoxypropyl  bromide  with  two 
noles  of  diethyl  amine  works  very  good  giving  80-90  percent 


Ids,  calcul 

ated  on  phenol 

^yprop3rl  bro: 

iide . 

To  prepare 

o 1 10  phenoxy  qi, 

X %J 

ityl  diethyl 

amine,  it  wa 

start  with 

phenoxypr  o pyl 

cyanide  arid 

reduce  it  to 

le  pnenoxy 

butyl  amine j by  means  o£  sodium  and  alcohol.  Yields  of  the 
phenoxybutyl  amine  were  obtained  between  4G  and  50  percent. 

The  modification  of  the  sodium  and  alcohol  reduction  as  carried 

out  by  Levene  and  C.llen”  was  tried  and  80  percent  yield  was 
tainedh  Levene  and  Alienas  modi  " . ' ion  required  five  eights 


as  much  sodium  and  one  fourth  as  much  absolute  alcohol  as  the 
Gammon  sodi  m and  alcohol  reduction  requires*  The  modification 
shortened  the  time  of  reduction  from  two  hours  to  twenty 

mdnut.es. 

The  phene  xybu  eg  1 amine  was  now  converted  to  the  phenoxybutyl 
diethyl  amine  by  means  of  ethyl  bromide  in  presence  of  sodium 
hydroxide.  One  mole  of  phenoxybutyl  amine  with  one  mole  of 
ethyl  bromide  a id  one  mole  of  30  percent  sodium  hydroxide  were 
allowed  to  react.  The  reacting  mixture,  was  then  treated  with 
one  more  mole  of  ethyl  bromide , and  one  and  one-fourth  moles  of 
sodi  e \ Iroxide.  7C-S0-  percent  yields  of  phenox}  ..  . yl  diethyl 
tar®  obtained,  calculated  on  the  basis  of  phenoxybutyl  a 

when  the  pfieno xypr o py 1 diethyl  amine  was  split  with  fuming 
' 2 irobroir.ic  acid,  it  -hi*;  not  split  to  give  phenol  and  the 
hydro bromide  of  hrompropyl  diethyl  amine  as  was  expected  but 
gave  phenol,  trims thyle  ie  br  'A  , and  the  hydro bromi de  of 
diethyl  amine. 

■C'HS  AoH 


a.  CjH5 

0<Ha-c«,-cHl-V  Nc^  + s 


H Br 


H 


V 


t Bv-cH »-C/h'CHvSv+ 

cx  Hj  i 

By 


In  the  same  manner  phenoxybutyl  diethyl  amine  split  with  fumi 
hydro bromic  acid  to  give  phenol,  tetramethylene  bromide,  and 
the  hydrobromide  of  diethyl  amine. 

Rraun  and  Be  s eke  a split  phenoxybutyl  amine  by  means  of 
ydrebromic  acid  Bp.lr.  1..02  in  a sealed  tube  on  the  water  hath 
to  give  phenol  and  tl  1 drobre  ids  o £ brorabutyl  amine. 

Both  the  pheraiaypr o py  1 diethyl  amine  and  phenoxybutyl  diet— 
h^rl  amine  and  phenoxybutyl  diethyl  amine  were  split  with  48 
percent  hydrohromic  acid  in  a reflux  on  the  steam  bath  to  rive 


3 


the  respective  hydrobromides  of  the  dialkylamino  alkyl  halides 

and  phenol. 

The  hydro  bromide  of  brompro.pyl  diethyl  amine  has  been 
prepared  in  70—75  percent  yields  k the  author  and  the  hydro- 
bromide of  brombutyl  diethyl  amine  has  been  split  from  phenoxy- 
butyl  diethyl  amine  by  means  of  hydro bromic  acid.  This  product 
has  not  been  purified  and  analyzed  but  there  is  practically  no 
doubt  as  to  its  being  the  hydro bromide  of  brombutyl  diethyl  amine* 


— 


. 


. 


4 


d*. 


FHSNO.TZFACrYL  DITTHYL  ...  IPS. 

15  grains  of  phenoxypropyl  bromide 
and  5*5  grams  of  diethyl  amine  were  dissolved  in  30  cc.  of  dry 
ether*  The  ether  solution  was  put  in  a flask  and  stoppered.  After 

standing  for  a da2;-,  a white  flaky  precipitate  formed.  This 

was 

late^fj  3 off  and  it  weighed  4 s*.  A melt in 

was  taken  and  it  melted,  at  205-210  degrees  (unc.)  Some  of  the 
hydro bromide  was  prepared  and  it  melted  at  207-210  (unc).  The 
precipitate  was  evidently  the  hydrobremide  of  diethyl  amine. 
Apparently  the  reaction  of  one  mole  of  phenoxypropyl  bromide, 
and  one  mole  of  diethyl  amine  did  not  react  as  was  expected,  to 
form  the  hydrobromide  of  phenoxypropyl  diethyl  amine.  The 
following  reaction  was  expected. 


-o-cHrchfCHt-Br  CxWy  kVo-  CH» c» 

fiV 


+ c -» 


'v* 


but  the  reaction  actually  took  place  as  follows', 


O-CH^-c  1-ffCHy-B  y 


Hr 


cM>rn 

I J *r 


The  next  step  was  to  try  one  mole  of  phenoxypropyl  bromide 
with  two  moles  of  diethyl  amine.  30  grams  of  phenoxypropyl 
bromide  and  20.5  grams  of  diethyl  amine  were  dissolved  in  70  cc. 
of  dry  ether.  After  standing  for  two  days  a white  precipitate 
• ydrobromide  of  diethyl  amine  formed.  T1  r&ro.hr 
was  filtered  off  and  it  weighed  15.5  grams.  The  ether  was 
distilled  from  the  filtrate  on  the  steam  bath.  The  residue  'which 

was  a heavy  liquid  was  vacuum  distilled.  The  greater  portion  of 
the  liquid  came  over  between  155-14'  3 wees  at  30  mm. pressure . 

•rt.  qualitative,  analysis  showed  that  nitrogen  was  present  in  the 


5 


distillate.  The  distillate  was  treated  with  dilute  hydrochloric 
acid  and  extracted  with  ether  to  remove  any  phenoxypropyl 
bromide  which  might  he  present*.  The  acid  solution  was  treated 
with  an  excess  of  25;'  sodium  hydroxide  which  freed  the  amine 
and  it  formed  in  a layer  at  the  top  of  the  solution.  The  amine 
layer  was  separated  and  vacuum  distilled,  nearly  all  the  amine 
distilled  over  between  130-140  degrees  at  70  mm. pressure, 
field  was  9 grams. 

This  method  of  preparation  requires  several  days  to  run. 
so  the  next  step  was  to  try  the  reaction  with  the  aid  of  heat. 
107  grams  of  pheno xypropyl  bromide  was  put  in  a SCO  cc.  round 
bottom  flash  with  a reflux  condenser.  A thermometer  was  introduc- 
ed thru  the  condenser  so  that  it  extended  into  the  phenoxypropyl 
bromide.  The  apparatus  was  placed  upon  a steam  bath  and  when 
the  phenoxypropyl  bromide  reached  40  degrees,  36.'"  grams  of 
diethyl  amine  was  added  slowly . At  first  no  reaction  was 

five  minutes,  the  t 

until  it  reache 4170  degrees  indicating  that  the  reaction  was 
talcing  place,  .after  15  minutes , the  temperature  declined  until 
It  reached  70  degrees.  The  flash  was  hep':  at  7.0— SO  degrees  on 
the  steam  bath  for  12  hours . A brownish-red  sirnpp  li quid  In d 
formed  to  which  100  cc.  of  30;$  sodium  hydroxide  was  added  and 
three  layers  formed.  The  upper  layer  was  colored  slightly 
yellow.  The  middle  layer  was  a brownish-red  color  and  the 
bottom  layer  was  nearly  coloress.  150  cc.  of  ether  was  added 
and  shakene.d  with  the  mixture.  The  upper  layer  was  soluble  in 
the  ether  while  the  middle,  and  bottom  layers  were  insoluble.  The 


5 


t 


• s ■•'tod.  The  ether  ms  distilled  from  the 

*j  j. 

s tier  layer  and  the  residual  liquid,  mss  vacuum  distilled.  It 
©8  sr  be  tween  degrees  at  2.1  ores  sura.  Yield  ms 

’7  n Is  liquid  had  a slight  odor  of  phenoxypropyl  ^raciidfe 

so  i^  was  dissolved  in  dilute  hjd]  larxc  an  id,  • sracted  with 

ether,  and  neutralised  wltl  25  di  \ 'kuxide.  II 
lag  or  was  scu  arr.ted  aid  distilled  under  vacuum,  it  came  over 
between  133—142  degrees  at  13  mm.  pressure.  Yield  was  37  gra  s. 
2.1 .7  -o  theory'  "based  on  phenoxypropyl  bromide. 

The  hydro chloride  of  the  amine  was  prepared  hy  passing  dry 
hydrogen  chloride  thru  the  amine  in  solution  of  dry  ether.  The 
hydrochloride  melted  between  93—102  degrees  (unc • ) 

The  middle  layer  was  separated  and  allowed  to  stand  for 
several  days  in  which  time  it  solidified,  in  attempt  was  made 
to  crystallise  it  from  absolute  alcohol  but  the  compound  would 
not  crystallize.  /7a ter  was  tried  next  because  the  compound 
was  quite  insoluble  in  cold  water.  In  boiling  water  it  readily 
passed  into  solution  and  upon  cooling  cooling,  it  did  not 

•stallise  at  once  but  aiter  srta  da  several  " us,.  Ion  • hits 
needle  cry stalls  formed.  n.F.  77.5-79  degrees  (unc.)  This 
compound  is  r quaternary  ammonium  salt  which  was  formed  as  a 
by-product,  "fb::  quaternary  ammonium  salt  is  diphenoxypropyl 
d iet hy  1 a:  m on i urn  b r o m ide. 

C^Hs-O-cHfCH^-cfK  PZciHf 

Analysis  of  this  compound  for  bromine  gave  good  checks  with  the 
theoretical  percentage.  The  analysis  was  run  hy  the  Tolhard 
method  for  determination  of  halo  ;ens. 


* 


7 

Sample  was  0^7000  grams.  16.85  oc.  of  0.0981  ' silver  nitrrte. 
Found  bromine  was  18.89y  Calculated  for  OooH-oCol.  Br 

is  13.95,0  bromine. 

The  bottom  layer  was  the  water  layer  which  contains  sodium 
chloride  and  sodium  hydroxide. 

3y  the  method  of  using  one  mole  of  phenoxypropyl  bromide 
with  one  ..ole  of  li  thyl  amine,  there  is  too  much  quaternary 
ammonium  salt  formed.  Tl  next  step  was  to  try  one  mole  of 
phenoxypropyl  bromide  with  two  moles  of  diethyl  amine. 

55  grams  of  diethyl  amine  was  placed  in  a 500  cc.  round 
bobtora  flakk  with  a reflux  condenser.  The  apparatus  was  placed 
on  the  steam  hath  and  the  diethyl  amine  was  heated  until  it 
began  to  boil.  Then  107  prams  of  phenoxypropyl  bromide  was 
added  slowly  from  a dropping  funnel.  A precipitate  formed  and 
also  a heavy  brown  sirup.  After  heating  on  the  steam  bath  for 
8 hours,  a very  sticky  semi-solid  formed.  To  this  was  added 
100  cc.  of  30p  sodium  hydroxide  and  three  layers  separated.  The 
middle  Layer  which  is  the  quaternary  ammonium:  salt  was  lurch, 
smaller  than  it  was  in  the  previous  run.  Benzene  was  added  to 
extract  the  amine  lender,  the  water  and  middle  layers  being 
insoluble  in  the  benzene.  The  benzene  layer  was  separated  and 
distilled  to  remove  the  benzene.  The  amine  was  vacuum  distilled 
and  it  came  over  between  140-1  ’5  degrees  at  IS  mm. pressure.  Yield. 

was  75  _rams.  7 8,4  percent  of  the  theoretical  amount.  The 
phenoxypropyl  diethyl  amine  was  not  purified  because  it  is  not 

necessary  to  have  it  pure  for  the  next  reaction.  A few  grams 
of  the  pure  phenoxypropyl  diethyl  amine  was  converted  into  the 
hydrochloride  by  means  of  passing  dry  hydrogen  chloride  thru  the 


, 


- 

' 


8. 


a. nine  in  dry  ether  solution*  The  hydrochloride  separates  as  a 
vghite  precipitate.  It  was  then  filtered  off  and  dried  in  a 
vacuum  desiccator  over  sulphuric  acid.  The  hydrochloride  was 
analyzed  for  chlorine  by  the  Volhard  method. 

Jeight  of  sample  was  0.5071  grams  19.93  cc.  of  0.1694  F silver 
nitrate  used.  Found  chlorine  was  14.41$,  Calculated  for 

i 

&13&22.0-N  81  3 -w.  Chlorine  is  14.56$.  It  can  safely  be.  said 
that  the  amine  is  pheno xypr opyl  diethyl  amine.  Specific  Gravity 
is  0.9442  at  20  degrees.  Index  of  refraction  at  20  degrees  is 
1.4937.  MJP.  of  the  hydrochloride  is  d 

The  simplest  and  best  method,  yielding  80—90$  yields  is  as 
follows.  73  grams  of  diethyl  amine  is  placed  in  a liter  flask 
with  a reflux  condenser.  It  is  heated  on  the  steam  bath  so  that 
the  diethyl  amine  refluxes.  Then  10Q  grams  of  pheno xypropyl 
bromide  is  added  thru  the  condenser  during  30  minutes.  A white 
precipitates  forms  which  causes  the  flask,  to  bump  a little.  The 
reaction  mixture  is  heated  for  12  hours  upon  the  steam  bath.  At 
the  end  of  this  time,  the  contents  of  the  flask  appears  to  be 
almost  solid.  The  contents  of  the  flask  are  shaken  well  with  200 
cc.of  dry  ether.  The  amine  dissolves  in  the  ether.  The  solid  is 
the  hydro bromide  of  diethyl  amine.  It  is  now  filtered  and  washed 
with  about  10 Q.  cc.  more  of  dry  ether.  The  ether  is  distilled 
from  the  ether  extract  and  the  amine  is  vacuum  distilled.  B.T, 
146—149  degrees  at  20  mm.  pressure.  Yields  on.  three  runs  were, 
81.5  grams  34.35$  theoretical,  83  grams  85$  theoretical,  90  gram 

theoretical.  This  method  gives  a fairly  pure  phenoxypropyl 
diethyl  amine  with  possibility  "of  a little  phenoxypropyl  bromide 
being  present  as  the  impurity.  In  order  to  get  a very  pure 


* t 


* 


o 

c* 

k ' <, 

phenoxypropyl  die th/1  amine , dissolve  it  in  dilute  hydrochloric 

acid  and  the  extract  with  ether  to  remove  the  phenoxypropyl 
bromide.  Add  an  excess  of  sodium  hydroxide , separate  the  anine 
layer  and  distill  under  vacuum.  Phis  purification  lowers  the 
yield  of  phenoxypropyl  diethyl  amine  about  lhn  mainly  due  to 

mechanical  losses. 


kRATIOH  CP  BEOI FAOPYL  DIETHYL  ALIBIS  HYDE  BBi  IDE. 

24  /rains  of  phenoxypropyl  diethyl  amine  was  placed  in  a 
100  cc. flask  with  a reflux  condenser  a id  00  prams  of  40 j 
hydrobromic  .cid  was  added.  This  mixture  was  refluxed  for  12 
hours  over  ; sn  flame.  The  contents  of  the  flask  war-  diluted 

wit]  IDO  sc.*  af  water  and  extracted  with  ether  to  remove  the 
phenol.  The  water  solution  was  evaporated  to  dryness.  The  solid 
was  dissolved  in  300  cc„  of  hot  benzene  and  upon  cooling  part  of 
it  settled  out  as  a white  solid.  This  white  solid  was  analyzed 
as  follows,  Q. 3.972  prams  of  the  white  solid  was  Ixed  with  0.500 
prams  of  benzoic  acid  and  10  prams  of  sodium,  peroxide.  This 
mixture  was  fused  in  a Farr  sulfur  bomb.  The  fused  mass  was 
dissolved  in  water  and  analyzed  for  bromine  by  the  Yolhard 
ethoC.  17.53  cc.of  0*0.981  silver  nitrate  used.  Precent  of 
bromine  found  was  33.8y.  Percentage  of  bromine  ln.br 
diethyl  amine  hydrobromide  is  58.10$ 

This  analysis  showed  that  the  splitting  of  phenoxypropyl 
diethyl 'amine  with  hydrobromic  acid  had  not  gone  to  completion. 

The  mixed  hydrobromides  of  brompropyl  diethyl  amine  and  phenoxy- 
propyl diethyl  amine  were  refluxed  for  16  hours  more  with  50 
.rams  of  fumin-  hydrobromic  acid.  The  contents  of  the  flask  were 


10 


extracted  with  ether  and  evaporated  to  dryness  which  left  a 
dark  brown  tarry  e ;?.ss,  This  mass  was  dried  in  a vacuum  desicc 
or  over  sulphuric  acid.  After  drying,  the  solid  was  dissolved 
in  boiling  absolute  alcohol.  It  was  then  cooled  and  dry  ether 
was  added  which  forced  out  the  hydrobromide.  The  ether  was 
decanted  which  carried  the  purer  hydrabromids  with  it..  The 
hydrobromide  was  filtered  and  dried.  It  had  a slight  brown  color 
The  melting  point  was  not  very  sharp  as  it  melted  over  a range 
from  78—88  degrees.  An  analysis  was  made  by  fusing  with  benzoic 
acid  and  sodium  peroxide.  The  bromine  was  then  determined' by 
tjge  Volhard  method. 

"/eight  of  sample  was  0.3209  grams.  24.46  cc .of  Q.Q981  K sir 
nitrate  used.  Found  bromine  was  59 *.07^.  Calculated  for  Gy, 
Hp7ti  , bromine  is  58.13,2. 

■ Another  run  was  made  by  taking  40  grams  of  phenoxypropyl 
diethyl  amine  and  50  grams  of  fuming  hydrobromic  acid  and 
refluxing  for  19  hours. 100  cc.of  water  was  added  to 'the  contents 
of  tbs  flask  a ad  part  of  it  was  insoluble  in  the  water,  leaving 
an  oily  liquid.  The  mixture  was  extracted  with  ether  which 
removed  the  oily  liquid  and  the  phenol.  The  water  solution  was 
evaporated  to  dryness.  The  hydrobromide  would  not  crystallize 
from  absolute  .alcohol  and  ether-. 

The  oily  liquid  was  chiefly  trimethyl ena  bromide  which 
indicates  that  the  phenoxypropyl  diethyl  amine  was  split  to  f 
give  phenol,  trimethylene  brc  iide,  and  the  hydrobromide  of 
diethyl  amine. 

It  is  apparent  that  fuming  hydrobromic  acid  is  too  strong 
and  the  temperature  top  high  for  the  formation  of  brompropyl 


11. 


diethyl  a line*  Ih  as  t<  a run  with  weaker  acid 

a id  a lower  temperature. 

The  hydro hro aide  of  phenoxypropyl  diethyl  amine  was  prepared 

by  treating  15  grams  og  phenoxypropyl  diethyl  amine  with  13 

grams  of  43,1  hydro’oromic  acid  and  evaporating  to  dryness  on  the 

steam  hath..  The  hydroorouiide  was  now  put  in  a refluxin  par at— 

us  with  45  grams  of  48$  hydrobro  mic  acid  and  heated  on  the  steam 

hath  for  19  hours.  About  100  cc.  of  water  was  aided  and  an  oily 

liquid  separated*  The  amount  of  this  oily  liquid  present  was 
than 

much  smaller  ..  when,  fuming  hydro  bromic  acid  was  used.  The 
mixture  was  extracted  with  ether  and  evaporated  to  dryness.  The 
hydro bromide  was  dissolved  in  a mininum  amount  of  boiling  ethyl 
acetate  and  upon  cooling  in  a mixture  of  sale  and  ice_,  the 
hydrobromide  crystallized.  It  was  then  filtered  off  and  washed 
three  times  with  dry  ether.  The  hydro bromide  was  dried  in  a 
vacuum  desiccator  over  sulphuric  acid.  It  melted  at  86-89 
degrees  §unc*)  Yield  of  14.5  grams.  72$  of  theoretical  calculat- 
ed on  basis  of  phenoxypropyl  diethyl  amine. 

Great  care  must  be  taken  that  the  hydrobromide  is  dry 
before  trying  to  crystallize  from  dry  ethyl  acetate  because 
a small  amount  of  water  will  hinder  the  crystallization. 

Ad  analysis  of  the  hydrobromide  of  brompropyl  diethyl  a ine 
was  made  by  determining  the  amount  of  bromine  which  is  combined 
in  the  form  of  the  hydrobromide  by  the  Yolhard  method. 

./eight  of  sample  was  0.5000  grams.  18.53  cc*of  0*0.981  IT  silver 
nitrate  used.  Bromine  found  was  29*16$.  Calculated  for  £7, 

Eiviji  j^rs.  . Bromine  is  29*09$ 


12 


/ 


FSEFARATrON  OF  PEZ^OXmVTn^^mZEl . 

TOO  grams'  of  phenoxypropyl  cyanide  was  dissolved  in  2 liter  s 
of  absolute  alcohol  and  placed  in  a 5 liter  round  bottom  flask, 
fitted  with  an  upright  condenser  of  large  bore.  200  grams  of 
sodium  was  added  slowly,  until  the  alcohol  began  to  boil  and 
then  fast  enough  to  keep  it  boiling  continually,  it  was  then 
heated  in  an  oil  bath  until  all  the  sodium  dissolved.  The  alcohol 
was  removed  by  steam  distillation.  The  phenoxybutyl  amine  was 
extracted  with  ether,  then  with  dilute  hydrochloric  acid  and 
freed  with  alkali.  It  was  now  vacuum  distilled.  B.F.  158—16 
degrees  at  33  mm  ..pressure*  Upon  two  runs  mate  there,  was  41  grams 


yield  which  is 
ical.  The  above 
the  low  yield's 
required. 


€0$  the  ore  tical  a 3 15  grams  which  is  43,*  theoret— 
procedure  was  not  very  satisfactory  because  of 
and  large  amounts  of  sodium  and  absolute  alcohol 


Another  method  was  tried  which  gave  ? good  yield,  about 
G2>j  theoretical  with  much  smaller  amounts  of  sodium  and  ah 
alcohol  required.  This  method  is  known:  as  Levsae  and  ..lien’s 
modification  _ . 300  cc.  of  dry  toluene  was  put  in  a 5 liter 
round  bottom  flask  and  123  grams  of  sodium  was  added.  The  fla^k 
was  hi  it  d ....  an  oil  bath.  ..hen  the  sodium  melted  , the  contents 
. C he  flask  were  stirred  very  rapidly  by  means  of 'a  mercury 
1 . stirring  was  continued  ~ 3 the  sodi 

was  broken  into  fii  , 3 oil  bath  was  re  a d i id  the 

Hum  was  allowed  to  solidify.  Aft  .r  t.3  : cc  ts  of  he-  f 1 sk 


had  led,  100.  grams  of  pher  oyl 

z d in  IOC  cc. of  absolute  alcohol,  was 
means  of  a dropping  funnel*.!? 


which  was  dissolv- 
added  to  the  sodium  by 
v/ as  required  for  this 


13, 

addition*  An  Ice  "bath  must  ' e ' ept  at  hand  so  as  to  rets  3 1 e 

reaction  when  it  joes  too  rapidly.  500  cc.of  absolute  alcohol 
was.  added  in  50  minutes'  and  the  st irring  was  continued  for  one- 
half  an  hour,.  Then  300  oo.of  water  was  added  slowly,. five  minutes 
being  required  for  this  addition  and  it  was  then  refluxed  on  the 
oil  hath  for  one-half  hour.  The  mixture  was  distilled  on  the 
steam  bath  until  all  the  : hoi  and  toluene  was  driven  off, 

•as  added  to  bring  the  volume  up  to  one  liter.  The 
amine  layer  was  separated  and  distilled  under  vacuum. B .P,  149— 151 
degrees  at  19  mm. pressure.  Yield  was  85  grams.  82,1  of  the 
theoretical  amount  oaZci  lated  on  the  phenoxypropyl  cyanide.  By 
t&is  method,  the  yield  was  doubled, about  five-eights  as  much 
sodium  and  one— fourth  as  much  absolute  alcohol  were  used.  This 
method  of  reduction  only  required  2.0  minutes  while  the  other 
method  took  about  twp  hours. 

FiSP.JuiTIOl-r  CF  K-mo:CYBUTYL  DIFT1IYL  AhllKB. 

85  grams  of  phenoxybutyl  amine  was  placed  in  a 500  cc. flask, 
and  55.5  grams  of  ethyl  bromide  and  20.6  ^rams  of  sodium 
hydroxide  in  water  solution  were  added.  The  mixture  was  shakened 
for  a short  time.  Heat -was  liberated  denoting  that  the  reaction 
was  taking  place.  The  flask  was  stoppered  and  allowed  to  stand 
for  a dapr.  55 _S  grams  of  ethyl  bromide  and  25  jrams  of  sodium 
hydroxide  are  added  with  shaking.  The  mixture  was  allowed  to 
stand  for  another  day.  The  contents  of  the  flask  are  boiled  in 
a reflux  for  one-half  hour.  Three  layers  formed  of  which  the 
top  layer  was  the  amine,  the  middle  was  probably  qtu  t raary 

ammonium  compound,  arm1  bottom  lap  ‘was  tl  s<  d'ium  h 3 Lie 
solution.  The  amine  is  extracted  with  ether  and  then  the  ether 


14 


was  distilled  off.  The  amine  was  distilled  und  r vacuum.  B.F. 
152-158  at  SI  mm. pres sure, and  with  another  run  Lie  B.F,  was  196- 
201  decrees  at  37  mm. pressure.  Yield  was  84  prams,  73m  of  the 
theoretical  amount.  Upon  another  run  with  smaller  quantities 
of  materials  33.3  grams  were  obtained,  80,4  theoretical  amount* 

A small  quantity  of  the  hydrochloride  of  the  phenoxybutyl 
diethyl  amine  was  prepared  by  passing  dry  hydropen  chloride  thru 
a solution  of  the  amine  in  dry  ether.  The  hydrochloride  was 
filtered  off  and  dried  in  a vacuum  desiccator.  U. P.118-120  (unc) 
The  hydrochloride  was  analyzed  for  chlorine  by  means  of  the 
Vo 1 hard  method  for  determination  of  halogens. 

Weight  of  sample  was  0..40Q3  grams.  15.43  cc.of  0».C(931  IT  silver 
nitrate  used.  Found  chlorine  was  13.424,  Calculated  for  0q • 
ij  Ql.  . Chlorine  is  13.77;'. 


P {EPARATIOR  OF  RRGMBUTYL  DIETHYL  'AMINE  HYD'RQBROMIDE. 

30  grams  of  phenoxybutyl  diethyl  amine  and  50  grams  of 
fuming  hydrobr omi c acid  were  refluxed  for  12  he  . XQC  cc.of 
water  was  added  to  the  contents  of  the  flask  and  all  of  the 
reacting  mixture  did  not  dissolve  but  left  an  oily  liquid.  The 
presence  of  this  oily  liquid  Indicated  that  the  phenoxybutyl 
diethyl  amine  split  to  give  phenol, tetramethylene  bromide , and 
the.  hydrobr  omi  de  of  diethyl  amine.  It  was  evident  that  the 
hydrobromide  had  split  too  far  aid  that  the  hydrobro  lie  acid  was 
too  strong  so  another  run  was  made  with  48,1  hydrobr  omi  c acid. 

The  hydrobromide  of  phenoxybutyl  diethyl  amine  was  prepared 
first,  by  treating  15  grams  of  phenoxybutyl  diethyl  amine  with 
15  -rams  of  48,2  hydrobromic  acid  and  it  was  evaporated  to  dryness 
on  the  steam  bath.  The  solid  was  placed  i:v  a flask  with  reflux 


15 


and  45  grates  of  48$  hydro  bromic  acid.  It  was  refluxed  for  on  the 
steam  bath  for  21  hours*  About  ICO  cc*of  r was  added  to  the 
contents  of  the  flask  and  an  oily  liquid  separated  • ’ ich  was 
very  much  smaller  in  quantity  as  compared  to  the  amount  which  is 
formed  when  fuming  hydrobromic  acid  is  used*  The  mixture  was 
extracted  with' ether  to  remove  the  ph  nol  and  tetramethylene 
bromide*  The  water  solution  was  evaporated  until  all  the  water 
was  removed.  Avery  thick  viscous  liquid  formed  which  v o .Id  not 
solidify  upon  cooling*  This  sirupy  liquid  is  pro bally  the 
hydrobromide  of  bromhutyl'  diethyl  amine*  The  liquid  was  placed 
in  a vacuum  desiccator  over  sulphuric  acid  for  a week  but  would 
not  solidify*.  Attempts  were  made  to  crystallize  it  from,  ethyl 
ac  u :e , absolute  alcohol  and  drv  ether  without  air~  success. 


16 


3u:.:.i,RYfc 

1*  ' 1 d3  .1  % m ' • has  been  prepared  in  80-10  percent 

yields  from  phenoxypropyl  bro  dde  and  di  thyl  •■mine. 

2...  3rompropyl  diethyl  anna  hydrabromidc  has  been  prepared  in 

70-80  percent  yields  by  the  splitting  of  phenoxypropyl  diethyl 
'amine  with  hydros ro lie  acid. 

3 ^ rhft  yield  of  phono xybutyl  amine  from  the  reduction  of  phenaxy- 
propyl  cyanide  has  been  increased  from  40-30  percent  yields 
to  80  percent  by  use  of  Levene  and  Allen-? s modification  of 
the  sodium  and  alcohol  reduction. 

4„  Fheno.xyb.utyl  diethyl  amine  has  been  prepared  in  70—80  percent 
yields  from  phenoxybutyl  amine. 

5 The  splitting  of  phenoxy butyl  diethyl  amine  to  the  hydrobrom— 
ide  of  brornbutyl  diethyl  amine  by  means  of  hydro  bromic  acid 
was  attempted  but  the  resulting  product  has  not  been  purified 
and  analysed. 

Diphenoxy propyl  diethyl  ammonium  bromide  was  isolated  as  a 
by-pro d'uo t from  the  preparation  of  phenoxypropyl  di  hyl  amine. 


.......  ft  . ■ - i*> 


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t 


17 


bibliography:. 

1.  Berichte  2A  3232 

2.  Berichte  2274 

3.  Journal  of  biological  Chemistry  27 

4.  Berichte  39  4121 


443 


